The development of a safe and effective HIV vaccine is an urgent priority. Live vector HIV vaccines represent a promising means of eliciting HIV-specific cellular and humoral immune responses. The factors that contribute to a potent HIV-specific immune response to live vector vaccines remain incompletely defined. The major hypothesis of the current proposal is that pseudovirion particle formation by live vector HIV vaccines enhances cellular and humoral immune responses through delivery of particulate antigen for antigen presentation in regional lymph nodes. Our laboratory has recently demonstrated that pseudovirion production by a canarypox vector increases cellular and humoral responses to HIV antigens by comparison with a matched vector that is deficient in particle formation. Experiments described in this proposal will determine if this property is applicable to MVA and adenovirus vectors. Experiments in Aim 1 will compare the immunogenicity of live vectors that are able to produce pseudovirions with matched vectors that lack the capacity to make pseudovirions. Of particular interest is the potential for pseudovirions expressed from live HIV vaccine vectors to present envelope glycoproteins in a native conformation and generate antibodies that will effectively bind and neutralize HIV particles. In Aim 2, the potential role of Vpu in enhancing immunogenicity of live Gag-Env vectors will be analyzed. Experiments in Aim 3 will test the hypothesis that pseudovirion-competent vectors produce antigen that more efficiently reaches regional lymphoid tissue. Together, these experiments will provide important insights into the role of pseudovirions in generating HIV-specific immune responses following live vector immunization. [unreadable] [unreadable]